Abstract Sleep abnormalities commonly occur among chronic cocaine users long after withdrawal. The withdrawal- associated sleep problems, including loss of sleep and worsened sleep quality, have been speculated to foster cocaine use and relapse. However, it is not well understood whether and how sleep-associated mechanisms may regulate the brain reward circuitry and impact relapse-like behaviors. In rats withdrawn from cocaine self- administration, there is persistent reduction in total sleep time and increased sleep fragmentation, resembling the changes in humans. Interestingly, experimentally increasing REM (without changing NREM) sleep after withdrawal reduces cocaine craving, suggesting REM sleep-associated mechanisms in this regulation. In the nucleus accumbens (NAc), a key brain region for reward processing, there is progressive accumulation of the GluA1-rich, calcium-permeable, AMPA receptors (CP-AMPARs) after long-term withdrawal from cocaine. These receptors critically contribute to the intensified cue-induced cocaine craving after long-term withdrawal. Importantly, sleep intervention that increases REM sleep time/duration leads to decreased CP-AMPARs in the NAc, which is accompanied by reduced cocaine craving after withdrawal. These results not only suggest NAc CP-AMPARs as key neuronal substrates that express sleep-mediated regulation of cocaine craving and relapse, but raise the important question ? how does REM sleep-associated mechanisms route to NAc CP- AMPARs? Accumulating evidence suggests that the melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) may critically contribute to the REM sleep-mediated effects. Activity of LH MCH neurons during sleep drives the initiation and/or maintenance of REM sleep. Moreover, MCH neurons project to the NAc, where MCH receptors are highly expressed; MCH receptor signaling in the NAc strongly regulates the phosphorylation and synaptic removal of GluA1-containing AMPARs. Preliminary results further show that LH MCH neurons exhibited reduced membrane excitability long after withdrawal from cocaine, whereas mimicking MCH release in the NAc after long-term withdrawal by intra-NAc infusion of MCH during the light (sleep) phase led to reductions of CP-AMPARs in the NAc and reduced cocaine craving during the subsequent dark (active) phase. Together, these results suggest that an increase in the activity of MCH neurons may be critical for both normalizing REM sleep and reducing cocaine craving after withdrawal. This application aims to test the hypothesis that enhancing the activity of LH MCH neurons during sleep will increase REM sleep time/duration and reduce cocaine craving after withdrawal. Expected results of the proposed research will identify a putative REM sleep-associated mechanism that modulates synaptic transmission within the brain reward circuitry and regulates cocaine craving after withdrawal. Given the close association between sleep disturbance and the co-morbid psychiatric diseases including drug addiction and depression, this application is highly relevant to the mission of the NIH.